tbuckley/cabot-search huggingface dataset:
DDEL-06. MICROGLIA REPAIR THE DISRUPTED BLOOD-BRAIN BARRIER FOLLOWING LOW-INTENSITY PULSED ULTRASOUND THROUGH P2RY12 SIGNALING
Authors: Karl Habashy, Victor Arrieta, Yu Luan, Kwang-Soo Kim, Silpol Dhiantravan, Hinda Najem, Mateo Gomez, Crismita Dmello, Li Chen, Ruth Saganty, Andrew Gould, Ye Hou, Amy Heimberger, Michael Canney, Roger Stupp, Feng Yue, Adam Sonabend
Journal: Neuro-Oncology (2023)

Abstract In a phase I clinical trial for patients with recurrent glioblastoma, we used an implantable ultrasound device for low-intensity pulsed ultrasound and microbubbles (LIPU/MB) to open the blood-brain barrier (BBB). This strategy increased parenchymal drug concentrations by 3.7- to 5.9-fold. Magnetic resonance imaging analysis with gadolinium injections at different timepoints post-sonication revealed that the BBB integrity began to restore within an hour post-sonication. To investigate the effect of LIPU/MB, we biopsied sonicated and non-sonicated peritumoral brain regions 45 minutes post-sonication before tumor resection in 7 patients. Single-cell RNA sequencing analysis revealed that sonicated microglia clustered separately and had enrichment of gene ontology terms related to the positive regulation of cell adhesion (p &amp;lt; 2x10-6), wound healing (p &amp;lt; 3x10-5), and regulation of vascular development and angiogenesis (p &amp;lt; 4x10-5). Upregulated genes included IL1B (log2fold-change 2.9, p &amp;lt; 1x10-140), PLAUR (log2fold-change 1.9, p &amp;lt; 2x10-177), and VEGFA (log2fold-change 1.8, p &amp;lt; 1x10-125). We also evaluated the spatial distribution of microglia in sonicated and non-sonicated samples by multiplex immunofluorescence. Analysis of 20 vessels per sample demonstrated that sonicated microglia accumulated around blood vessels, averaging at 14 μm from CD31+ cells, compared to 45 μm in non-sonicated biopsies (p &amp;lt; 0.01). Based on previous reports of P2RY12-dependent microglial migration and repair of the BBB, we evaluated the effect of P2RY12 inhibition with clopidogrel on BBB repair post-sonication in mice. Permeability assay with fluorescein revealed that the BBB was 80% (p &amp;lt; 0.001) and 50% (p &amp;lt; 0.05) more permeable at 10 and 45 minutes post-sonication in clopidogrel-treated mice, respectively. This work provides human data supporting the role of microglia in the repair of the BBB, previously described in animals, and provides preclinical and clinical evidence for the role of these cells in the rapid restoration of vascular integrity post-LIPU/MB in humans.
CTNI-65. INVESTIGATING SAFETY AND EFFICACY OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA - FIRST RESULTS OF THE PRICOTTF PHASE I/II TRIAL
Authors: Sied Kebir, Lazaros Lazaridis, Teresa Schmidt, Christoph Oster, Jonas Feldheim, Daniela Pierscianek, Martin Proescholdt, Peter Hau, Anca-Ligia Grosu, Dietmar Krex, Ulrich Sure, Björn Scheffler, Christoph Kleinschnitz, Christoph Pöttgen, Martin Stuschke, Martin Glas
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND A synergistic inhibiting effect on glioblastoma cell proliferation was reported for the combination of TTFields and radiotherapy. Based on these preclinical findings, we performed the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy. Material and METHODS In this phase I/II trial, TTFields therapy was initiated following surgery and continued throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was allowed at recurrence. Radiotherapy was conducted with arrays applied on the patients’ scalp. Safety and tolerance are the study’s primary endpoint, determined by a selection of pre-specified treatment-limiting toxicities (TLTs). RESULTS A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of ≥ common toxicity criteria (CTC) grade 3 was comparable to that of established glioblastoma trials. Notably, skin toxicity of ≥ CTC grade 3 was uncommon (n = 2, 6%). No patient developed TLTs. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion. Notably, on multivariable Cox regression, the number of days with TTFields adherence &amp;gt;23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p = 0.008). CONCLUSION The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.
NIMG-57. PERFORMANCE OF DEEP LEARNING IN <i>MGMT</i> PROMOTER METHYLATION STATUS PREDICTION USING BRAIN MRI: RESULTS FROM A LARGE COHORT OF IDH-WILDTYPE GLIOMAS TESTED BY A SINGLE METHYLATION ASSAY
Authors: Gian Marco Conte, Mana Moassefi, Shahriar Faghani, Francesco Sanvito, Paul Decker, Sani H Kizilbash, Jeanette Eckel-Passow, Cristine Ida, Bradley Erickson
Journal: Neuro-Oncology (2023)

Abstract There have been several attempts to predict the MGMT promoter methylation status of gliomas using deep learning (DL), with mixed results. These studies did not account for IDH mutation status and did not utilize a uniform methylation assay, introducing potential confounders in the experimental design. We assessed the performance of DL applied to brain MRI to predict the MGMT promoter methylation status of IDH-wildtype gliomas tested with a standardized assay. We included 539 IDH-wildtype gliomas tested with real-time methylation-specific PCR from 2017-2022; 205 (38%) were MGMT promoter methylated. The assay targets 8 downstream MGMT CpG sites using ACTB as control; methylation status is determined based on the difference of PCR crossing-point values: methylated if difference &amp;lt; 5, unmethylated if difference &amp;gt; 7, indeterminate otherwise. We used post-contrast T1 and T2 MRIs as inputs for our models trained using stratified 5-fold cross-validation, 400 epochs, batch size of 16, a learning rate scheduler starting at 10-3, weighted binary cross-entropy loss, and AdamW optimizer. We repeated the experiments using two 3D DL architectures (DenseNet121 and EfficientNetB0) and two image preprocessing pipelines: the BraTS protocol and one that uses padding instead of registration to an MRI atlas, keeping constant other experimental variables. For Densenet121, the best cross-validation AUROCC and F1-score (median, median absolute deviation) were 0.67 (0.06), 0.59 (0.02) using the BraTS protocol, and 0.67 (0.06), 0.58 (0.01) using padding. For EfficientNetB0, were 0.67 (0.02), 0.66 (0.01) using the BraTS protocol and 0.67 (0.01), 0.68 (0.01) using padding. Our findings suggest that it is unlikely that DL models trained on brain MRI can predict the MGMT promoter methylation of IDH-wildtype gliomas. Importantly, our study is the first to focus on an IDH-wildtype adult diffuse glioma cohort tested with a single, standardized MGMT methylation assay, eliminating the variability introduced by different assays and IDH status.
EPCO-47. HETEROZYGOUS CDKN2A LOSS IS ASSOCIATED WITH HIGHER RECURRENCE AND LOWER SURVIVAL IN HIGH-, BUT NOT LOW-GRADE MENINGIOMAS
Authors: Joanna Tabor, Miguel Millares Chavez, Joseph O'Brien, Saul Morales-Valero, Alexandros Pappajohn, Declan McGuone, Zeynep Erson-Omay, Katsuhito Yasuno, Murat Gunel, Jennifer Moliterno
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Homozygous loss of CDKN2A/B is known to be associated with more aggressive meningiomas and is now considered in the updated criteria for WHO grading. The relevance of heterozygous loss (hetloss) of CDKN2A/B is less clear and the potential association of hetloss CDKN2A with aggressive meningioma phenotype remains underexplored. OBJECTIVE We sought to understand the clinical associations of hetloss CDKN2A meningiomas. METHODS Clinical and whole exome sequencing (WES) data for patients who underwent resection of sporadic meningiomas were reviewed and analyzed. RESULTS Of the 564 meningiomas included, 16 tumors harbored a heterozygous mutation of CDKN2A; 6 of these were low-grade (WHO grade I) and 10 were high-grade (grade II or III). CDKN2A hetloss meningiomas were more likely to be high-grade (p=0.03) and to be diagnosed at older ages (p=0.04) than wild type (WT). Compared to high-grade hetloss meningiomas, low-grade ones were more likely to have elevated proliferative index (p=0.04) and were more common along the skull base (p=0.04). Low-grade meningiomas with hetloss CDKN2A compared to WT ones were more likely to be symptomatic (p=0.023); there was no difference in the tumor make-up or progression free survival (PFS) (p=0.4). High-grade hetloss CDKN2A meningiomas, however, had higher mitotic count (p=0.014), increased chromosomal instability (p=0.004), and higher recurrence rates (p&amp;lt; 0.001), as well as shorter PFS (p&amp;lt; 0.001) and decreased overall survival (OS) (p=0.002), compared to high-grade WT meningiomas. These findings remained significant amongst high-grade hetloss CDKN2A meningiomas even when controlling for underlying NF2 mutation. CONCLUSION Heterozygous loss of CDKN2A is associated with more aggressive histological and genomic characteristics in high-grade meningiomas. Additionally, high-grade meningiomas with hetloss CDKN2A differ from those without the mutation with higher recurrence rates and shorter PFS and lower OS, irrespective of underlying somatic NF2 mutation. These findings may have clinical implications for management.
NIMG-88. THALLIUM 201 SINGLE PHOTON EMISSION CT (TI-SPECT) FOR DIFFERENTIATION OF MALIGNANT VERSUS BENIGN NERVOUS SYSTEM SPACE OCCUPYING LESIONS: A RETROSPECTIVE STUDY, SYSTEMATIC REVIEW, AND META-ANALYSIS
Authors: Mark Willy Mondia, Anisah Hayaminnah Alonto, Nicole Girlyn Pang, Francis Manuel Resma, John Kenneth Gacula, Arnel Pauco, Annabell Chua, Julette Marie Batara
Journal: Neuro-Oncology (2023)

Abstract Importance Thallium-201 single-photon emission computed tomography (TI-SPECT) imaging has been used historically to distinguish malignant cerebral neoplasms from infectious etiologies. Objectives Our study aims to review existing literature and conduct a retrospective study and meta-analysis on the use of TI-SPECT to differentiate malignant from non-malignant nervous system lesions. Data Sources A retrospective study on use of TI-SPECT in differentiating malignant versus benign nervous system masses was conducted in two tertiary hospitals in the Philippines. Systematic review of relevant studies regarding TI-SPECT for brain and spinal cord lesions was also done. Meta-analysis was performed to generate pooled sensitivity and specificity. Study Selection All study types published in the English language were included – randomized controlled trials (RCTs), prospective/retrospective cohort studies, and case series and reports; abstract only studies were excluded. Studies that involved either pediatric and adult cases were considered. Data Extraction and Synthesis The study complied with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) Guidelines. Main Outcome and Measure The primary outcome was sensitivity and specificity of TI-SPECT. This involved getting correlation of positive and negative thallium scan uptake with either biopsy results (if available) or diagnosis via clinical response to treatment (i.e. whether cases that were managed as infection or demyelination showed improvement on follow-up). RESULTS: Thirty-two (32) articles were qualitatively described and 25 datasets were subjected to meta-analysis. Pooled sensitivity and specificity were 0.89 (95% CI: 0.82-0.94) and 0.82 (95% CI: 0.74-0.88), respectively with an area under the curve (AUC) for diagnostic accuracy of 0.92. CONCLUSION: and Relevance Thallium scans may be utilized to discriminate malignant from benign nervous system lesions, especially, in cases with a &amp;gt;80% pre-test probability. Further studies are needed to validate this findings.
DDEL-13. CILIA INHIBITORS SYNERGIZE WITH TEMOZOLOMIDE TO DRAMATICALLY IMPROVE SURVIVAL IN ORTHOTOPIC MURINE MODELS OF GLIOBLASTOMA
Authors: Benjamin Umlauf
Journal: Neuro-Oncology (2023)

Abstract Patients with malignant brain tumors such as glioblastoma face a poor prognosis with a median survival of less than two years. Recent glymphatic studies demonstrate the interconnectivity between the fluid in the brain parenchymal and ventricular spaces. We reasoned enhancing the accumulation of a drug in the cerebral spinal fluid (CSF) of the ventricular space will also enhance the accumulation of the drug in the parenchyma where a GBM resides. To improve drug accumulation in the CSF, we modulated the motility of ependymal cell cilia. Ependymal cells coat the ventricles and display motile cilia that mechanically propel CSF through the ventricular space. Impairing ciliary motion could slow down CSF turnover without affecting the overall amount of CSF in the brain and central nervous system. To test these hypotheses, we identified FDA-approved therapeutics that are known to impair airway cilia as a “side effect.” Seven candidate drugs were administered into the ventricle of mice bearing orthotopic GBM in combination with systemic temozolomide. Five of the seven cilia-inhibiting drugs significantly improved overall survival when combined with temozolomide compared to controls. The lead candidate, lidocaine, demonstrated a synergistic relationship with temozolomide, and 100% of animals treated with the combination survived to the study endpoint tumor free. We demonstrate lidocaine can impair cilia motility in vitro and in vivo. Combining intraventricular lidocaine with temozolomide is well tolerated and results in a 2.8-fold increase in brain temozolomide concentration per dose compared to controls. Finally, we validate these data in two human PDX orthotopic xenograft GBM murine models, including an un-methylated MGMT GBM that became sensitive to temozolomide with the combination treatment. These studies offer a new concept for treating malignant brain tumors and potentially a scheme to improve the treatment of additional encephalopathies in the future.
DISP-05. UNDERSTANDING THE INDIVIDUAL CHALLENGES AND EXPERIENCES OF YOUNG ADULTS WITH A DIAGNOSIS OF GLIOBLASTOMA AND HIGH-GRADE ASTROCYTOMA
Authors: Kaviya Devaraja, Jonathan Avery, Maureen Daniels, Kim Edelstein, Abha Gupta, Derek Tsang
Journal: Neuro-Oncology (2023)

Abstract High-grade gliomas are highly aggressive and fatal primary malignant brain tumors in adults with ineffective existing treatment methods. Older adults are greatly impacted by high-grade gliomas as they are more common among this population. Young adults (individuals aged 18-39) are uniquely impacted by high-grade glioma. However, there are few resources and information available to address these unique needs. The purpose of this study is to explore the lived experience of this population to inform the development of resources to help address their specific needs. A qualitative descriptive design drawing on thematic analysis was chosen to conduct and analyze interviews with young adult high-grade glioma patients at the Princess Margaret Cancer Center. Interviews focused on patient experiences as a high-grade glioma patient at Princess Margaret Cancer Center, the challenges they face and changes they would like implemented. A coding framework was created to determine emerging themes using qualitative data analysis software NVivo 10. To date, 5 interviews (1 men; 4 women; age range 19-37) have been completed. Interviews described the challenges living with high-grade glioma as a young adult and the changes in resources and support services patients would like implemented. Experiences highlighted 1) difficulty accepting this change in life and disruptions brought upon life goals and plans at the young adult age; 2) an overall lack of young adult high-grade glioma specific education, advocacy and support resources 3) A call for more community building and connecting so patients do not feel alone through this diagnosis. These patient interviews highlight a connection between the young adult age and high-grade glioma diagnosis and the challenges experienced and the services required. These results will serve as the foundation to advocate for the creation of tools that cater to patient needs of young adult high-grade glioma patients.
BIOM-01. PROGNOSTIC IMPLICATIONS OF SMALL CELL LUNG CANCER (SCLC) TRANSCRIPTIONAL SUBTYPING FOR CENTRAL NERVOUS SYSTEM (CNS) METASTASES
Authors: Anna Skakodub, Kathryn Tringale, Jacklynn Egger, Jordan Eichholz, Yao Yu, Daniel Gomez, Andreas Rimner, Bob Li, Yoshiya Yamada, Jessica Wilcox, Nelson Moss, Brandon Imber, Natasha Rekhtman, Marina Baine, Charles Rudin, Luke Pike
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Small cell lung cancer (SCLC) is characterized by a high propensity for brain metastases (BM) and is associated with a poor prognosis. Subtypes characterized by high versus low neuroendocrine states (expressing ASCL1 or NEUROD1) have been identified. This study aims to evaluate the influence of transcription factor-defined SCLC subtypes on the incidence and outcomes of BM. METHODS We identified 164 patients with SCLC based on their ASCL1 and NEUROD1 expression status by immunohistochemistry. Four transcriptional subtypes were defined: ASCL1+/NEUROD1- (A+/N-), ASCL1+/NEUROD1+ (A+/N+), ASCL1-/NEUROD1+ (A-/N+), and ASCL1-/NEUROD1- (A-/N-). Cumulative incidence competing risk analyses examined the incidence of central nervous system (CNS) progression. Cox proportional hazards models were utilized to assess both overall survival (OS) and CNS progression-free survival (CNS-PFS). RESULTS Out of 164 patients, the majority fell into either A+/N- or A+/N+ subtypes (n = 62, n = 63, respectively). BM were detected at the time of diagnosis in 12% (20/164) of patients, while 18% (29/164) developed BM later. In two distinct cohorts of patients (initially free from BM and with de novo BM at diagnosis), the 12-month cumulative incidence of CNS progression was numerically highest for the A+/N- subtype (HR = 11.8, 95%CI: 4.7-22.4, and HR = 44, 95%CI: 10.5-74.7, respectively). OS in both A+/N- and A-/N+ subtypes was worse compared to the A+/N+ subtype (HR = 1.62, 95%CI: 1.03-2.56, and HR = 1.63, 95%CI: 1.06-2.60, respectively). Similarly, CNS-PFS was poorer in same A+/N- and A-/N+ subtypes (HR = 3.10, 95%CI: 1.39-6.93, and HR = 3.38. 95% CI: 1.49-7.67) when compared to A+/N+. CONCLUSIONS This study is the first to explore CNS-specific outcomes based on transcription factor SCLC subtypes. Among patients without BM at SCLC diagnosis, those exclusively expressing ASCL1 or NEUROD1 demonstrated poorer outcomes than those with co-expression. Further investigation is warranted to elucidate the implications of SCLC subtyping, ultimately facilitating tailored disease management.
DDDR-23. COMBINATION THERAPY WITH PACLITAXEL, CARBOPLATIN, AND LOW-INTENSITY ULTRASOUND FOR RECURRENT GLIOBLASTOMA: RATIONALE FOR ONGOING PHASE II CLINICAL TRIAL
Authors: Karl Habashy, Crismita Dmello, Li Chen, Victor Arrieta, Kwang-Soo Kim, Andrew Gould, Guillaume Bouchoux, Michael Canney, Roger Stupp, Adam Sonabend
Journal: Neuro-Oncology (2023)

Abstract We recently participated in phase 1/2 clinical trials where patients with recurrent glioblastoma received surgery for tumor resection followed by implantation of an ultrasound device into a skull window for subsequent repeated blood-brain barrier opening and concomitant delivery of chemotherapy (Sonabend et al., Lancet Oncology). Intraoperative experiments demonstrated a 3.7 to 5.9-fold increase in the brain concentration of paclitaxel (NCT04528680) and carboplatin (NCT03744026). Building on the pharmacokinetics and safety of these trial results, and the historical use of paclitaxel and carboplatin as a combination in other cancers, we investigated the efficacy of this combination in glioblastoma models. First, we analyzed the cytotoxicity of both drugs in vitro against five human cell lines and six patient-derived xenografts as monotherapy and in combination at concentrations derived from our human intraoperative pharmacokinetic studies. Cell lines exhibited little overlap in susceptibility to the drugs, with 27% being exclusively susceptible to one of the two drugs tested. The combination covered 81% of cell lines, compared to 54% covered with monotherapy. We also assessed for synergy using the Loewe model and recorded synergy in 55% of cells. We then evaluated the benefit of this combination in vivo in two xenograft models (MES83 and GBM6) where drugs were administered with ultrasound. Combination therapy proved more effective than monotherapy with either of the drugs, led to distinct effects on cell cycle progression and enhanced DNA damage and apoptosis. We conclude that the addition of carboplatin to paclitaxel may be more effective than monotherapy with paclitaxel, which we performed in our phase 1 trial. This combination is supported by its efficacy in other cancers, and the synergy and independent susceptibility to each drug in glioma models. The safety and efficacy of this approach are currently under investigation in an ongoing phase II trial for patients with recurrent GBM (NCT04528680).
DISP-04. EXPLORING ENGAGEMENT IN LOW GRADE GLIOMA GENOMIC RESEARCH: A COMPARATIVE ANALYSIS OF THREE APPROACHES
Authors: Bethany Kwan, Juliana Barnard, Carly Ritger, Anowara Begum, Liz Salmi, Rudy Fischmann, Sandra Garcia-Hernandez, Nestelynn Gay, Ricardo Gonzalez-Fisher, Laura Helmkamp, Kevin Johnson, Lindsay Lennox, Guy Lipof, Jasmyn Ostmeyer, Ifeoma Perkins, Laura Pyle, Jenna Reno, Taylor Roth, Elizabeth Claus, Roel Verhaak, Matthew DeCamp
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Engaging patients and care partners in research planning and conduct improves equity and patient-centeredness of research. Determining the most effective engagement methods remains challenging. This study evaluated participation and experience using three engagement methods with the Low Grade Glioma (LGG) Registry’s OPTIMUM project, part of the Participant Engagement in Cancer Genome Sequencing (PE-CGS) Network. METHODS We evaluated participation and experience among participants in LGG Registry Research Advisory Council (RAC) meetings, Twitter (“tweet chats”), and Facebook discussions across four engagement activities. Participants completed validated engagement experience surveys, including the Public &amp; Patient Engagement Evaluation Tool (PPEET), Research Engagement Survey Tool (REST), Patient Engagement in Research Scale (PEIRS-22), and the Trust in Medical Researchers scale. Researchers recorded discussions and performed qualitative analyses across groups. RESULTS RAC engagements involved 25 unique participants representing diverse backgrounds, while tweet chats and Facebook discussions had 197 and 133 participants, respectively. Post-engagement surveys (n = 52 post-engagement 1; n = 40 post-engagement 4) showed no statistically significant differences between engagement approaches in the overall meaningfulness of engagement on PEIRS-22 or REST scales, nor were there differences in post-engagement 1 trust. RAC members rated PEIRS-22 procedural requirements more positively and reported recalling a wide range of expressed views more than social media participants. Conversely, RAC members gave less positive ratings on PPEET items related to feeling heard. Qualitative findings highlighted differences in the nature of interactions across groups, but agreement around trust and similar recommendations for promoting participation in genomic research across engagement methods.